1. Field of the Invention
This invention relates to a water-based formulation and a process for coating aspirin granules that results in coated granules that may be compressed into tablets and that release aspirin with approximately zero-order kinetics over a period extending five to eight hours. The invention further relates to rapidly disintegrating tablets comprising said coated aspirin granules, a process for the manufacture of said tablets, and a method of using said tablets for the prevention and treatment of human vascular occlusive diseases. Specifically the invention relates to processes for and products from the coating of aspirin granules with a neutral, insoluble but permeable, elastic film and the fashioning of tablets from said coated granules by compressing with disintegrants, antiadherents, lubricants and preferentially-crushable granules.
2. Information Disclosure
It is known in the art that aspirin significantly decreases platelet adhesiveness by acetylating cyclooxygenase in platelets. This biochemical action manifests itself in statistically significant protection from vascular occlusive events among patients given oral aspirin. It is also known that, at the doses given in most clinical trials, aspirin inhibits endothelial cyclooxygenase. Because the effects in these two tissues are believed to antagonize one another, there has been a search for a dose and dosage form of aspirin that might be effective in suppressing the production of thromboxane B.sub.2 (TX) by platelets without suppressing the production of prostacyclin (PC) by endothelial cells.
More recently Reilly and FitzGerald [Clinical Research 32, 320A(1984)] have suggested that if hepatic extraction were virtually complete with low doses of aspirin, repeated administration of low doses might permit cumulative presystemic inhibition of TX while protecting endothelial cyclooxygenase from exposure to aspirin. They reported that 1 mg of aspirin given every 30 minutes for 10 hours to human volunteers resulted in a decrease in serum TX by 66% at 10 hours while urinary PC was unaltered. Similarly, Jakubowski et al [J. Lab. Clin. Med. 108, 616-621(1986)] reported that granular, enteric-coated aspirin, when given three times a day in 27 mg doses to human volunteers, resulted in 96% inhibition of serum TX generation without detectable levels of aspirin in the systemic circulation. Formal clinical trials with low-dose, slow-release aspirin to treat or prevent transient ischemic attacks, myocardial infarction and related vascular occlusive events were suggested by Bochner and Lloyd [Clin. Sci. 71, 625-631 (1986)].
Until my discovery, no low-dose, controlled-release formulation for aspirin was known. Methods and formulations in the literature have suggested ways that one might approach the problem, but none of them addresses the five parallel requirements that I believe are necessary for large scale production and ultimate commercial distribution to the patient population: (1) A dosage form must provide a controlled, linear, near-zero-order release of low doses of aspirin; the release should be relatively independent of pH so that drug release is not governed by the pH changes that occur during gastrointestinal transit. (2) The components of the dosage form, including any coatings and films, must not interact or alter with time; the rate of release and total dose released must be unaffected by the conditions or duration of normal storage. (3) The dosage form should be in the form of a tablet to avoid the hazards of tampering that are associated with capsules. (4) The final dosage form must have minimal residence time in the stomach to avoid the gastric irritation associated with aspirin. (5) The process used to prepare the dosage form cannot utilize non-aqueous solvents, which require extensive and expensive mitigation measures to avoid environmentally unsatisfactory or hazardous conditions, but the aqueous process must not compromise the stability of the water-sensitive aspirin.
Thus, for example, Sothmann and Marttila (U.S. Pat. No. 4,351,825) describe a sustained-release, water-based system using an acrylate/methacrylate copolymer for coating tabletable granules of 50 mg of phenylpropanolamine hydrochloride and 100 mg of verapamil hydrocloride but there is no indication that the medication is released with zero-order kinetics nor is any duration longer than 3 hours demonstrated. The process is not described in detail, but it does not appear applicable to water-sensitive medicaments such as aspirin. Further, monolithic (also known as matrix) tablets are produced and the problem of gastric residence time is thus not addressed.
Dunn and Lampard (U.S. Pat. No. 4,308,251) describe 650 mg and 800 mg aspirin tablets that exhibit zero-order release in vitro and closely approximate zero-order absorption in vivo, but the tablets are monolithic and the disintegration times shown in the patent are all greater than two hours; the problem of gastric residence time is unrecognized. Further, the medicament tablets are prepared "by dissolving the release controlling agent in suitable organic solvent or solvent mixture such as methylene chloride and denatured alcohol [1:1(v/v)]. Other suitable solvents include but are not limited to, lower aliphatic alcohols such as methanol, isopropanol, n-propanol, etc., acetone and lower aliphatic ketones, such as methylethylketone, chloroform, carbon tetrachloride, ethyl acetate and nonchlorinated hydrocarbons."
Seth (European Application No. 250,648) describes a multiple unit dosage form of ibuprofen in which microspheres of ibuprofen are coated with Eudragit.RTM. E30D ethyl acrylate/methyl methacrylate copolymer, and compressed into tablets containing not less than 600 mg of ibuprofen. The tablets release ibuprofen at an approximately zero-order rate for a period of ten hours; the tablets are said to release a flow of microspheres continously into the intestines from the stomach and this flow is said to be largely independent of the subsequent emptying of the stomach; the coated microspheres are said to display their retard-effect throughout the entire duration of transit. The technique for preparing the microspheres requires mixing an aqueous mixture of ibuprofen, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose, putting the resulting mixture through an extruder and a spheronizer and drying the resulting spheres at 45.degree. C. This is a process that is not feasible with water-sensitive medicaments such as aspirin; in the case of aspirin the amount of salicylic acid formed by hydrolysis during this process would be expected to fall well outside the allowed limits. Seth then describes a process of spray-coating a layer of pure Eudragit.RTM.E30D. This process, while manageable when the particles have been deliberately made into hard microspheres, cannot be practiced on irregular granules such as aspirin on a commercial scale. Further Seth does not address the unique problems of low-dose dosage forms; the application states that the need which Seth's discovery satisfies is for a dosage form which contains higher doses than 300 or 400 mg. (page 2, line 17-20). Seth also does not address the question of long-term stability of the release rate.
Schor et al. (U.S. Pat. No. 4,389,393) describe 650 mg aspirin tablets that use hydroxypropylmethylcellulose to provide zero-order release with a duration of 8 hours, and without need for a solvent. However, the lowest release rate described in 65 mg per hour and the tablets are monolithic. It is well known to persons familiar with the art that release rate, tablet size, tablet shape, and dose of medicament have a complex relationship monolithic tablets; thus a 650 mg matrix tablet cannot be reduced to a 40 to 100 mg dose without unpredictably altering the release rate--perhaps even precluding zero-order release. Accordingly, I have observed that no combination of HPMC and ethylcellulose could be coated on aspirin granules to provide tabletable granules with a zero-order release rate of 5-15 mg/hr. When the HPMC/ethylcellulose ratio was adjusted to produce the proper release rate, the coating did not survive compression, and the resulting tablets produced an unacceptable, large, initial burst of aspirin. Additionally, Schor does not recognize the problem of gastric residence time.
Lerk (U.S. Pat. No. 4,244,941) describes a constant-release composition which produces tablets, requires no solvent, and provides a linear release rate approximating zero-order over a period up to five hours. However, the composition only works with highly water-soluble medicaments. Sulfanilamide, which is twice as soluble as aspirin, is the least soluble medicament for which an example is provided, and its release rate is impractically slow. (4.5 mg per hour).
Powell and Patel (U.S. Pat. No. 4,361,545) delineate the importance of zero-order release, and describe a tablet composition that provides zero-order release over periods of 5 to 8 hours for medicaments having the solubility properties of aspirin. The zero-order release depends upon a phenomenon of controlled surface erosion in a monolithic tablet and no tablets containing less than 300 mg of active ingredient are described. Thus, neither the problem of gastric residence time nor the problem of scale down to low-dose is addressed.
Hennig and Kala [Pharmazie 41, 814-815 (1986)] describe the coating of aspirin granules of 1.07 mm with an aqueous dispersion of Eudragit.RTM.E30D and PEG 6000. The resulting particles have a zero-order release rate of 7.16 mg per hour over a period up to 8 hours; however, at 8 hours only 30 to 40% of the aspirin has been released, and there is no indication that the granules so produced could be compressed into a tablet.
Ventouras (European Application No. 213083) describes tablets containing 320 and 860 mg of a compound of methylxanthine medicaments in granules coated with Eudragit.RTM.E30D, compressed with tableting aids, and coated with Eudragit.RTM.E30D, lactose, talc, polysorbate and optionally with pigments. The tablets show zero-order release of methylxanthines over a period of 8 hours. Ventouras indicates that the tablet coating may be modified to control permeability by the inclusion of other water soluble fillers in place of the lactose of the example. Such water-soluble fillers discussed on page [3 paragraph 4] include: "Sodium chloride or a sugar, particularly lactose, fructose or D-mannit, [sic] or sorbitol or polyvinylpyrrolidone or a derivative thereof, or dextrane [sic] compounds of different molecular weight; or a swellable filler, e.g. hydroxypropylmethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose, e.g. Pharmacoat.RTM.-603, or an antisticking agent, e.g. talcum, or an emulsifier, e.g. polysorbate (Tween.RTM.-80), or a coloring pigment, e.g. indigotin lake or a metal oxide, e.g. iron oxide, such as red iron oxide or yellow iron oxide, or titanium dioxide; or a plasticiser, e.g. polyethylene glycol, such as Lutrol E-400 (BASF)." Since he is not administering aspirin, Ventouras does not address the problems of gastric residence time, and a tablet coated with E30D will remain a monolith. The problem of extending the technology to administer low doses is unappreciated: in fact the release curves for the 2 doses (FIGS. 2 and 3 of EP Application No. 213083) indicate a drop in total medicament delivered from about 85% at the 860 mg dose to about 70% at the 320 mg dose.
Kjrnaes and Linnemann (U.S. Pat. No. 4,713,248) describe the coating of potassium chloride crystals in a fluid bed process with Eudragit.RTM.E30D, hydroxypropylmethylcellulose and talc. The resulting coated particles may be compressed into tablets to provide tablets that release the same percent of medicament as the coated particles at one hour, indicating that the particles were compressed without substantial fracture of the control-release coating. Kjrnaes and Linnemann also recognize the problem of storage stability, but do not address it with a singlecoat particle. They describe a heat treating process which imparts storage stability and provides tablets with approximately zero-order release kinetics up to six hours; however, the particles that are heat treated have a second coating of HPMC and talc applied over the Eudragit.RTM. coat. A second patent (U.S. Pat. No. 4,716,041) also to Kjrnaes et al. states (column 6, line 31 to 35 and line 53 to 59) in reference to coatings containing Eudragit.RTM.E30D, HPMC, talc and optionally a hydrophobic substance: "In most cases, it has been found that, when subjected to the elevated temperatures necessary to obtain the effect desired above, the inner film layer tends to become tacky (adhesive) causing an undesirable agglomeration of the units. . . In both instances, ie. both when the substance incorporated in the coating and when the film-forming agent itself causes adhesion, it is therefore, necessary to provide the units with an additional, protective layer which is composed of a substance or a mixture of substances which is anti-adhesive at elevated temperatures and, preferably, also imparts flowability to the coated units." And, in fact, I have observed that if sodium chloride is deleted from the formulation of the present invention, the aspirin granules coated only with Eudragit.RTM., HPMC, and talc tend to agglomerate in the fluid bed coating process even in the absence of additional heat for curing.
Ventouras (U.S. Pat. No. 4,728,513) describes heat-treated granules of a compound of methylxanthine medicaments coated with a 6:1 mixture of ethyl acrylate/methyl methacrylate copolymer (Eudragit.RTM.E30D) and ethylcellulose (Aquacoat.RTM.ECD-30) followed by a top coat of ethylcellulose. The granules are stable, the release rate being essentially unaffected by storage 1 month at 35.degree. C. and only slightly depressed by storage 1 month at 50.degree. C. The granules are compressed into tablets by the use of conventional technology, utilizing art-known fillers, binders, disintegrants, and lubricants. The resulting tablets disintegrate very rapidly and release methylxanthines at approximately zero-order for 8 hours; however, only about 65% of the 900 mg dose is released by 8 hours.
Thus until my invention no one had addressed the problem of efficiently achieving controlled release (5 to 15 mg/hr for 8 hours) of aspirin from a low-dose tablet. Further, the systems described in the prior art that provide essentially zero-order, 5 to 8 hour release for non-aspirin medicaments cannot be extended to the aspirin problem without violating one or more of the requirements satisfied by my invention.
All of the systems described in the prior art that have been applied to aspirin sought stable, non-irritating, or sustained release of doses larger than 300 mg. Sustained-release products generally attempt to generate constant blood levels of a therapeutic agent from one administration of the agent to the next. The focus of my invention is not sustained release, but controlled release. According to my invention, the systemic blood levels of aspirin do not rise above 100 ng/mL at any time during the medication cycle. The duration of release of aspirin is of concern to my invention only indirectly in that it is a dependent variable resulting from the interplay of two required parameters: (1) the total dose must be sufficient to acylate a therapeutically useful proportion of platelet thromboxane synthetase, and (2) the rate of release must be low enough to allow virtually complete presystemic clearance.